Psoriasis is one of the most frequent skin diseases, affecting 1-3% of the Caucasian population worldwide (Barker, J. N. W. N., (1994), Bailliere's Clin. Rheumatol. 8, 429-437.). This complex disease is characterized by alterations in a variety of different cells. These include epidermal keratinocyte hyperproliferation and altered differentiation indicated by focal parakeratosis (cell nuclei in stratum corneum), aberrant expression of the hyperproliferation-associated keratin pair 6/16 (Stoler, A., et al., (1988), J. Cell Biol. 107, 427-446; Weiss, R. A., et al., (1984), J. Cell Biol. 98, 1397-1406), involucrin and filaggrin (Bernard, B. A. et al., (1986), Br. J. Dermatol. 114, 279-283; Dover, R. and Watt, F. M., (1987), J. Invest. Dermatol. 89, 349-352.; Ishida-Yamamnoto, A. and Iizuka, H., (1995), J. Invest. Dermatol. 104, 391-395), and integrin adhesion molecules (VLA-3, 5 and 6, .alpha..sup.6 .beta..sub.4) (Hertle, M. D., et al., (1992), J. Clin. Invest. 89, 1982-1901; Kellner, J., et al., (1992), Br. J. Dermatol. 125, 211-215). In addition, de-novo expression of major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1, CD54) by keratinocytes is observed (Barker, J. N. W. N., et al., (1990), J. Clin. Invest. 85, 605-608; Gottlieb, A. B., et al., (1986), J. Exp. Med. 164, 1013-1028; Griffiths, C. E. M., et al., (1989), J. Am. Acad. Dermatol. 20, 617-629; Nickoloff, B. J., et al., (1990), J. Invest. Dermatol. 94, 151S-157S; Veale, D., et al., (1995), Br. J. Deimatol. 132, 32-38). Endothelial cells also are hyperproliferative resulting in angiogenesis and dilation (Detmar, M., et al., (1994), J. Exp. Med. 180, 1141-1146; Goodfield, M., et al., (1994), Br. J. Dermatol. 131, 808-813; Malhotra, R., et al., (1989), Lab. Invest. 61, 162-168; Mordovtsev, V. N. and Albanova, V. I., (1989), Am. J. Dermatopathol. 11, 33-42) and express increased levels of ICAM-1, E-selectin (CD62E) and vascular cell adhesion molecule-1 (VCAM-1, CD106) (Das, P. K., et al., (1994), Acta Derm.Venereol. Supplementum 186, 21-22) as well as MHC class II (Bjerke, J. R., et al., (1988), Acta Derm. Venereol. 68, 306-311). Finally, a mixed leukocytic infiltrate is seen composed of activated T-lymphocytes which produce inflammatory cytokines (Ramirez-Bosca, A., et al., (1988), Br. J. Dermatol. 119, 587-595; Schlaak, J. F., et al., (1994), J. Invest. Dermatol. 102, 145-149), neutrophils within the dermis and formning Munro's microabscesses in the epidermis (Christophers, E., and Sterry, W. (1993). Psoriasis. In Dermatology in General Medicine, T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Freedberg and K. F. Austen, eds. (New York: McGraw-Hill, Inc.), pp. 489-514.), and an increased number of dermal mast cells (Brody, I., (1986), Upsala J. Med. Sci. 91, 1-16; Brody, I., (1984), J. Invest. Dermnatol. 82, 460-4; Rothe, M. J., et al., (1990), J. Am. Acad. Dermatol. 23, 615-24; Schubert, C. and Christophers, E., (1985), Arch. Dermatol. Res. 277, 352-358; Toruniowa, B. and Jablonska, S. (1988), Arch. Dermatol. Res. 280, 189-193; van de Kerkhof, P. C., et al., (1995), Skin Pharmacol. 8, 25-29). Intracutaneous secretion of cytokines is thought to mediate some or all of the tissue alterations seen in psoriasis. These cytokines include tumor necrosis factor-.alpha. (TNF.alpha.) and interleukin-1 (IL-1) (Kupper, T. S., (1990), J. Clin. Invest. 86, 1783-1786); interferon-.gamma. (IFN.gamma.) (Barker, J. N. W. N., et al., (1991), J. Dermatol. Sci. 2, 106-111; Gottlieb, A. B., et al., (1988), J. Exp. Med. 167, 670-675; Livden, J. K., et al., (1989), Arch. Dermatol. Res. 281, 392-397), IL-6 (Castells-Rodellas, A., et al., (1992), Acta Derm.Venereol. 72, 165-168; Grossman, R. M., et al., (1989), Proc. Natl. Acad. Sci. USA 86, 6367-6371; Neuner, P., et al., (1991), J. Invest. Dermatol. 97,27-33), IL-8 (Barker, J. N., et al., (1991), Am. J. Pathol. 139, 869-876), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) (Detmar, M., et al., (1994), J. Exp. Med. 180, 1141-1146), and transforming growth factor-.alpha. (TGF.alpha.) (Elder, J. T., et al., (1989), Science 243, 811-814; Gottlieb, A. B., et al., (1988), J. Exp. Med. 167, 670-675; Prinz, J. C., et al., (1994), Eur. J. Immunol. 24, 593-598).
Over the past decade, research into the pathophysiology of psoriasis has focused primarily on immunologic mechanisms and evidence is accumulating that this disease has an immunological basis. However, it has not been convincingly determined if the primary defect that results in psoriasis is an immunologic disorder or resides within the epithelium (Barker, J. N. W. N., (1994), Bailliere's Clin. Rheumatol. 8, 429-437; Christophers, E., and Sterry, W. (1993). Psoriasis. In Dermatology in General Medicine, T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Freedberg and K. F. Austen, eds. (New York: McGraw-Hill, Inc.), pp. 489-514). Abnormal immune regulation is suggested by the frequent association of psoriasis with the expression of certain MHC alleles including -B13, -B17, -Bw57 and -Cw6 (Russell, T. J., et al., (1972), N. Engl. J. Med. 287, 738-740; Tiilikainen, A., et al., (1980), J. Dermatol. 102, 179; Watson, W., et al., (1972), Arch. Dermatol. 105, 197-207; White, S. H., et al., (1972), N. Engl. J. Med. 287, 740-743), the improvement of psoriatic lesions by treatment with immunosuppressive agents such as cyclosporin A (Ellis, C. N., et al., (1986), J. Am. Med. Assoc. 256, 3110-3116; Mueller, W. and Herrmann, B., (1979), N. Engl. J. Med. 301, 555) and the lymphocyte-specific toxin DAB389 IL-2 (Gottlieb, J. L., et al., (1995), Nature Med. 1, 442-447), the possible linkage of a psoriasis susceptibility gene with a gene involved in IL-2 regulation (Tomfohrde, J., et al., (1994), Science 264, 1141-1145), and the failure of psoriasis to recur after bone marrow transplantation (Eedy, D. J., et al., (1990), Br. Med. J. 300, 908; Jowitt, S. N., et al., (1990), Br. Med. J. 300, 1398-1399). However, underlying epidermal and/or dermal defects are suggested by altered keratinocyte cell cycle and differentiation (Gelfant, S. (1982), Cell Tissue Kinet. 15, 393-397; Weinstein, G. D., et al., (1985), J. Invest. Dermatol. 84, 579-583), by aberrant expression of adhesion molecules by keratinocytes and endothelial cells (Das, P. K., et al., (1994), Acta Derm.Venereol. Supplementum 186, 21-22; Nickoloff, B. J., et al., (1990), J. Invest. Dermatol. 94, 151S-157S; Petzelbauer, P., et al., (1994), J. Invest. Dermatol. 103, 300-305; Veale, D., et al., (1995), Br. J. Dermatol. 132, 32-38; Wakita, H. and Takigawa, M., (1994), Arch. Dermatol. 130, 457-463), and by the abnormal expression of protooncogenes within keratinocytes (Elder, J. T., et al., (1990), J. Invest. Dermatol. 94, 19-25).
Research into the pathogenesis underlying the complex and intertwined alterations in psoriatic skin lesions has been severely hampered by the lack of appropriate animal models (Grammer, S. F., and Streilein, J. W. (1994), The immune system in cutaneous disease: the search for a mouse model of the immunopathology of psoriasis. In Handbook of mouse mutations with skin and hair abnormalities. Animal models and biomedical tools., J. P. Sundberg, ed. (Boca Raton, Ann Arbor, London, Tokyo: CRC Press), pp. 143-153; Nickoloff, B. J., et al., (1995), Am. J. Pathol. 146, 580-588: Vallat, V. P., et al., (1994), J. Exp. Med. 180, 283-296). Several investigators have produced transgenic animals in which increased expression of cytokines, adhesion molecules or other proteins in the skin results in epithelial hyperproliferation and altered differentiation (Carroll, J. M., et al., (1995), Cell 83, 957-968; D'Armiento, J., et al., (1995), Mol. Cell. Biol. 15, 5732-5739; Groves, R. W., et al., (1995), Proc. Natl. Acad. Sci. USA 92, 11874-11878; Guo, L. et al., (1993), EMBO J. 12, 973-986; Hammer, R. E., et al., (1990), Cell 63, 1099-1112; Takahashi, K., et al., (1994), J. Cell Biol. 127, 505-520; Vassar, R. and Fuchs, E., (1991), Genes Dev. 5, 714-727; Wilson, J. B., et al., (1990), Cell 61, 1315-1327). In some of these animals, an inflammatory reaction and/or dilation of blood vessels also occur in response to alterations in the epidermis (Groves, R. W., et al., (1995), Proc. Natl. Acad. Sci. USA 92, 11874-11878; Wilson, J. B., et al., (1990), Cell 61, 1315-1327; Carroll, J. M., et al., (1995), Cell 83, 957-968; Hammer, R. E., et al., (1990), Cell 63, 1099-1112). In addition, several mice with spontaneous mutations develop some features like those seen in human psoriasis (Grammer, S. F., and Streilein, J. W. (1994), The immune system in cutaneous disease: the search for a mouse model of the immunopathology of psoriasis. In Handbook of mouse mutations with skin and hair abnormalities. Animal models and biomedical tools., J. P. Sundberg, ed. (Boca Raton, Ann Arbor, London, Tokyo: CRC Press), pp. 143-153; Sundberg et al., (1993), Immunol. Invest. 22:389-401; Sundberg et al., (1990), J. Invest. Dermatol. 95:62s-63s; Brown and Hardy, (1988), Clin. Exp. Dermatol. 13:74-77; Gates and Karasek, (1965), Science 148:1471-1473; HogenEsch et al., "The chronic proliferative dermatitis (cpd) mutation, chromosome?" In: Handbook of mouse mutations with skin and hair abnormalities, Animal models and biomedical tools, J. P. Sundberg (ed.), CRC Press, Boca Raton, pp. 217-220 (1994).
Of note, one animal model has been produced which reportedly results from a primary immunologic abnormality. Expression of human HLA-B27 and .beta..sub.2 microglobulin in transgenic rats (HLA-B27 transgenic rats) reportedly results in the development of inflammation at many sites, including the gastrointestinal tract, joints, male genital tract, heart and skin (Hammer, R. E., et al., (1990) Cell 63:1099-1112). While some features of psoriasis are reported to occur in the skin of these HLA-B27 transgenic rats, others have not been noted, including dermal angiogenesis and blood vessel dilation as well as cutaneous mast cell infiltration. In addition, even for those HLA-B27 transgenic lines expressing the highest copy number, the skin changes reportedly did not appear until the animals were eighteen weeks old. Moreover, in one of these high copy number transgenic lines, reportedly only 50% of the transgenic animals were affected as late as twenty-five weeks of age (Taurog, J. D., et al., (1993) J. Immunol. 150:4168-4178). Thus, the transgenic HLA-B27 model is inadequate for screening therapeutic agents for treating an inflammatory skin condition because the skin changes reported for the HLA-B27 transgenic lines only occur in more mature animals with only moderate frequency. In another animal model reported for psoriasis, human psoriatic skin is transplanted onto the skin of a scid mouse. In these animal models, the transplanted skin grafts reportedly implant with greater than 85% graft survival and continued to exhibit psoriatic features for at least six weeks after transplantation (Nickoloff, B. J., et al., (1995), Amer. J. Pathol. 146:580-588; Boehncke, W.-H., et al., (1994), Arch. Dermatol. Res. 286:325-330). However, this animal model is difficult to utilize as a screening method for therapeutic agents as it requires human skin for transplantation to generate the model. Thus, there are no prior models of psoriasis in which the clinical and histopathological phenotype are known to develop as the result of a primary immunologic abnormality, in which 100% of the animal models are affected within two months and which do not require the use of human skin for model generation.
In view of the foregoing, there is still a need for an improved model for screening agents that are useful for treating an inflammatory skin condition. In particular, there is still a need for an improved model for psoriasis, which model mimics the immunopathological basis of psoriasis, occurs rapidly in virtually all test animals, and does not require the use of human skin to generate the model.